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WO1992002487A1 - Nouveau compose de diamine et agent de protection contre les lesions cerebrales contenant un tel compose - Google Patents

Nouveau compose de diamine et agent de protection contre les lesions cerebrales contenant un tel compose Download PDF

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Publication number
WO1992002487A1
WO1992002487A1 PCT/JP1990/000970 JP9000970W WO9202487A1 WO 1992002487 A1 WO1992002487 A1 WO 1992002487A1 JP 9000970 W JP9000970 W JP 9000970W WO 9202487 A1 WO9202487 A1 WO 9202487A1
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WO
WIPO (PCT)
Prior art keywords
group
same
compound
different
cerebral
Prior art date
Application number
PCT/JP1990/000970
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English (en)
Japanese (ja)
Inventor
Seiichi Sato
Kiyoshi Kawamura
Yosio Takahashi
Koichiro Watanabe
Sadahiro Shimizu
Tomio Ohta
Original Assignee
Kowa Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU60565/90A priority Critical patent/AU647034C/en
Priority to CA002087604A priority patent/CA2087604C/fr
Priority to DK90910895.3T priority patent/DK0541798T3/da
Priority to HU9300228A priority patent/HU220592B1/hu
Priority to KR1019930700135A priority patent/KR0171569B1/ko
Priority to EP90910895A priority patent/EP0541798B1/fr
Priority to DE69023928T priority patent/DE69023928T2/de
Priority to US07/966,142 priority patent/US5389630A/en
Application filed by Kowa Co., Ltd. filed Critical Kowa Co., Ltd.
Priority to ES90910895T priority patent/ES2081996T3/es
Priority to RU9093005056A priority patent/RU2045522C1/ru
Priority to AT90910895T priority patent/ATE130842T1/de
Publication of WO1992002487A1 publication Critical patent/WO1992002487A1/fr
Priority to FI930360A priority patent/FI112649B/fi
Priority to NO930328A priority patent/NO179322C/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/49—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/30—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups

Definitions

  • Novel diamine compound and brain protective agent containing it is a novel diamine compound and brain protective agent containing it
  • the present invention relates to a novel diamine compound or an acid addition salt thereof and a cerebral protective agent containing the same, and more particularly to a medicament having an excellent cerebral protective effect and preventing or improving various cerebral dysfunctions.
  • the present invention relates to a diamine compound or an acid addition salt thereof, which is useful as such, and a protective agent containing the same.
  • cerebral dysfunction In recent years, the number of patients with various cerebral dysfunctions is increasing with the increase in the aging population. Specific examples of such cerebral dysfunction include cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, transient cerebral ischemic attack, cerebral dysfunction associated with cerebrovascular disorder, and the like.
  • the causes of the dysfunction are thought to be mainly metabolic disorders such as decreased cerebral blood flow, insufficient oxygen in the blood, and hypoglycemia.
  • the present invention relates to the following general formula (I):
  • R !, R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxy group.
  • R 7 and R 8 are the same or different and represent a lower alkyl group, or both are combined to represent an alkylene group having 1 to 4 carbon atoms
  • a and A ′ are the same or different and are a single bond, one 0-, -NH-, one NHC0 ⁇ , - C0NH-, one NHC00 ⁇ , one NHC0NH-, - SO 2 NH- or - COS- was shown (- denotes a bond to Y or Y '), Y and Y 'are the same or different and each represents a lower alkylene group or a lower alkenylene group. Show)
  • the compound (I) of the present invention has an excellent cerebral protective effect, is highly safe, and exerts a strong effect even by oral administration, and thus is useful as a cerebral protective agent.
  • the lower alkyl group represented by R 3 to R 8 those having 1 to 6 carbon atoms are preferable, and a methyl group, an ethyl group, an n-propyl group, an isopropyl group Buildings are particularly preferred.
  • the alkyl moiety in the lower alkoxy group, lower alkoxy group, lower alkoxycarbonyl group, and lower alkylsulfonyloxy group represented by R 1 to R 6 is the same as described above, and has 1 to 6 carbon atoms.
  • the halogen atom is preferably a fluorine atom, a bromine atom, a chlorine atom, or the like.
  • the lower alkylene group and lower alkylene group represented by Y and Y ' are preferably straight-chain or branched-chain ones having 1 to 8 carbon atoms.
  • particularly preferred compounds (I) of the present invention include, for example, those represented by the following general formula (I ').
  • R to R 6 ′ represent a lower alkoxy group
  • the compound (I) of the present invention can be produced, for example, by any one of the following methods (1) to (9).
  • X represents a halogen atom, main Shiruokishi group or preparative Shiruoki sheet group, 1 ⁇ ⁇ 1 3, R 7, R 8, A and Y are same as the] a method (1), the compound ([pi ) Is reacted with the ethylenediamine derivative (m) to produce the compound (IV) of the present invention.
  • C This method (1) is similar to that of the compound (I) of the present invention. That is, R, R 2 , R 3 , A and Y are each applicable to the production of a compound (IV) in which R ”R 5 , Res A ′ and Y ′ are the same, and A (A ′) and Y There is no restriction on the type of (Y ').
  • the reaction proceeds in a suitable solvent, preferably in the presence of a base, at room temperature to 200 ° C. for several minutes to 10 hours.
  • Solvents used at this time include ethers such as getyl ether, dioxane, tetrahydrofuran, and the like; black-mouthed form, dichloromethane, carbon tetrachloride, benzene, toluene, and the like.
  • Hydrocarbons such as ruthene; phenolic phenols such as methanol, ethanol, and n-bromophenol; pyridine, dimethylformamide, dimethylsulfoxide, water, and the like. .
  • the base examples include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, and calcium hydroxide; triethylamine, diisoprovirethylamine, and diisopropylamine; -t-Butylamine, dimethyla Organic bases such as minopyridine, virolizinopyridin and the like can be mentioned.
  • Method (2) is a method in which the compound ( ⁇ ) is reacted with a diamine derivative (V). This is a method for producing the compound (I) of the present invention.
  • This method (2) can be applied irrespective of the type of the target compound (I).
  • the reaction proceeds under the same conditions as in the above method (1).
  • Method (3) is a method for producing a compound (VIII) of the present invention having a urethane bond by reacting a phenyl succinate derivative (VI) with a dihydroxyxamine (W).
  • This method (3) uses the compound of the present invention Compound (Cor) of (I) wherein R !, R 2 , R 3 and Y force are the same as R 5 , R 6 and Y ′, respectively, and A and A ′ are —NHC00— Applicable to the manufacture of
  • the reaction is carried out by stirring the compound (VI) and the compound (W) in a solvent similar to the method (1), preferably a hydrocarbon, at 50 to 200 ° C for 10 minutes to 5 hours. Progress.
  • the raw material phenyl succinate derivative (VI) can be obtained, for example, by reacting a corresponding benzoyl halide with azurized sodium.
  • the method (4) is a method for producing the compound (X) of the present invention by reacting the phenyl succinate derivative (VI) with an alcohol ( ⁇ ).
  • This method (4) can be applied to the production of the compound (X) of the present compound (I) wherein A is —NHC00—.
  • the reaction proceeds under the same conditions as in the above method (3).
  • the method (5) is a method for producing the compound of the present invention () by reacting an amine (XI) with a carboxylic acid (II).
  • a carboxylic acid II
  • the Chi No present compound (I), 'Ri same der and, A and A' R 2, R 3 and Y are each R 6, R e and Y gar NHC0- It can be applied to the production of compound (M).
  • an acid amide bond formation reaction used in general peptide synthesis can be applied.
  • the condensing agent in the method (a) for example, dicyclohexyl benzoylamide, N, N'-diskinimidyl carmide, N, N'-ka It is possible to use rubinilmidazole, diphenylphosphoryl azide, etc.
  • the reaction conditions differ depending on the condensing agent used.For example, dicyclohexyl rubodiimide is used.
  • the carboxylic acid () is reacted with dicyclohexyl carboximide in a solvent, and the amide (XI) is added thereto.
  • the reaction is completed by stirring for days.
  • the solvent used in this case include those described in the above method (1).
  • Examples of the reactive derivative of the carboxylic acid () in the method (b) include an acid halide, an acid anhydride, a mixed acid anhydride, an activated ester, and an acid azide.
  • Examples of the reactive derivative of the amine (XI) in the method (c) include an isocyanate and a phosphazo compound.
  • R 3 R 8 is the same as above for Y, Y ′ and A ′
  • Method (6) is a method for producing the compound of the present invention by reacting the carboxylic acid (S7) with the carboxylic acid (S7).
  • This method (6) can be applied to the production of the compound (XV) of the present compound (I) wherein A is —NHC0 ⁇ .
  • the reaction can be performed under the same conditions as in method (5).
  • Method (7) is based on reacting the amide (XI) with the compound (XVI). This is a method for producing the compound (XVII) of the present invention. This method (7) is intended for the production of a compound (XVII) in which R 2 , R 3 and Y are the same as R ′′ R 5 , R 6 and Y ′, respectively, and A and A ′ are —NH—. Yes.
  • reaction is carried out I'm ⁇ Mi emissions such (XI) with the compound (XVI) the same solvent as mentioned in the method (1), in the this stirring 1 to 20 hours at -30 to 200 e C .
  • B is C0X '
  • S0 2 X' ( X in here 'represents a halogen atom) or indicates NC0
  • A''one C0Nh ⁇ shows an S0 2 NH- or one NHC0NH- , R to R 3 , R 7 , R 8 and Y are as defined above)
  • the method (8) is a method for producing the compound (XX) of the present invention by reacting the compound (XVI) with an amine (XDO.
  • This method ( 8 ) is based on the method of the present invention. Akira the Hare Chi R] of the compound (I), 'Ri same der and, Alpha and a' R 2, R 3 and Y are each R "R 5, R 6 and Y gar C0NH-, one S0 2 NH ⁇ Alternatively, it can be applied to the production of compound (XX) which is one NHC0NH—.
  • the reaction is carried out by stirring the compound (V1D) and the amines (XIX) in the same solvent as described in the method (1) at -30 to 10 (TC for 10 minutes to 10 hours).
  • the present invention provides a method for producing the compound (II) of the present invention.
  • This method (9) can be applied to the production of the compound (II) of the present invention (I) in which C is —C0NH—, 1 S0 2 NH— or 1 NHC0NH—.
  • the reaction can be performed under the same conditions as in method (8).
  • the obtained compound (I) of the present invention can be separated and purified by a conventional method, but is preferably carried out by appropriately combining salt exchange, solvent extraction, chromatography, and the like. .
  • the compound (I) of the present invention obtained as described above can be converted into an acid addition salt by a conventional method, if necessary.
  • the acid include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, and hydrobromic acid; acetic acid, lactic acid, succinic acid, tartaric acid, lingic acid, maleic acid, citric acid, and fumaric acid.
  • Organic acids such as acid, methansulfonate, and toluenesulfonate are exemplified.
  • the thus-obtained compound (I) of the present invention or an acid addition salt thereof has excellent brain-protective activity and is a compound having low toxicity.
  • tablets, capsules, granules, powders, injections, suppositories and the like are prepared using appropriate excipients, carriers, diluents and the like. It can be administered orally or parenterally as a form, but the oral form is particularly preferred. These can be produced by a method known per se.
  • the compound (I) of the present invention can be prepared by excipients such as starch, mannitol, lactose, etc .; : Microcrystalline cellulose, cal Disintegrators such as boxymethylcellulose calcium; lubricants such as talc and magnesium stearate; and fluidity improvers such as light gay anhydride, etc. are appropriately combined and formulated. be able to.
  • excipients such as starch, mannitol, lactose, etc .
  • Microcrystalline cellulose, cal Disintegrators such as boxymethylcellulose calcium
  • lubricants such as talc and magnesium stearate
  • fluidity improvers such as light gay anhydride, etc.
  • the compound (I) of the present invention varies depending on age, symptoms and the like, but it is usually preferable to orally administer 10 to 3,000 mg / day in 1 to 3 divided doses.
  • reaction mixture was dissolved in ethyl acetate, washed with water and extracted with diluted hydrochloric acid. After basification with sodium hydroxide, extraction was carried out with a black form, the black form layer was washed with water and dried, and the solvent was distilled off to obtain 20.1 g of a crude product. This was purified by silica gel chromatography, then maleic acid salt was recrystallized by a conventional method, and recrystallized from methanol-ether to obtain 5.5 g of the desired product. Was done. Melting point: 181-184.
  • Example 10 The compound obtained in Example 10 was converted into an oxalate by a conventional method, and then acetylated using acetic anhydride and pyridin. The compound was converted into dimaleate according to a conventional method, and recrystallized from ethanol-ether to obtain 4.8 g of the intended product.
  • ⁇ -Trobenzoylk Mouth lid Dissolve L g in 22mfl of acetone and add a solution of sodium azide in 5.2mfl of water under ice-cooling and stirring. The mixture was stirred at room temperature for 1 hour. Acetone was distilled off from the reaction solution, and the residue was dissolved by adding a cross-linked form, washed with water and dried, and then distilled off the mixed form to obtain a crude acid azide compound.
  • Example 55 The following compounds were obtained using the method of Example 52, 53 or 54 above.
  • Example 55 The following compounds were obtained using the method of Example 52, 53 or 54 above.
  • mice weighing 20 to 27 g were used as 10 mice per group.
  • the test compound was orally administered (PO) as a 0.5% methylcellulose suspension 60 minutes after administration, and intraperitoneal administration (ip) 30 minutes after hypoxia, the survival time was increased. It was measured.
  • Hypoxia was achieved by placing one animal in a 300 mfl clear plastic container, into which a mixture of 95% nitrogen and 5% oxygen flowed at a rate of 80_fi / hr and passed through a hole in the side wall. Spilled out.
  • the survival time was defined as the time from the start of the inflow of the gas mixture until the respiratory movement stopped, and is shown in Table 1 as a percentage change with respect to the survival time of the untreated group.
  • mice Male ddY mice weighing 23 to 31 g were used in 10 groups.
  • test compound was orally administered as a 0.5% methylcellulose suspension 1 hour after administration, and 15 minutes after intraperitoneal administration, 20 mg of lithium cyanide 3 mg / kg was injected into the tail vein via the tail vein. Dosed in seconds. The time from the start of the administration of lithium cyanide to the cessation of breathing was measured, and the% change relative to that of the untreated group was determined. The results are shown in Table 2
  • test compound was administered subcutaneously at 30 mg / kg 60 minutes and 30 minutes before carotid artery ligation.
  • Idebenone as a control was administered intraperitoneally at 150 mg / kg under the same conditions.
  • Table 3 shows the mortality rate 72 hours after resumption of blood flow.
  • Sic about 10 weeks old: Five male rats per group were used. The test compound was suspended in 5% arabia gum, and behavioral observation was performed at 0.5, 1, 2, and 4 hours after oral administration of 300 or 100 mg / kg, and the animals were bred and observed for 3 days thereafter.
  • the compounds of Examples 1, 9, 11, and 52 all showed no behavioral abnormalities and no death by oral administration of 300 and 100 mg / kg.
  • the compound (I) of the present invention has an excellent cerebral protective effect, is highly safe, and exerts a strong effect even by oral administration, and is therefore useful as a cerebral protective agent. Therefore, a drug containing it can be effectively used for amelioration or prevention of progression of cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, transient cerebral ischemic attack, cerebral dysfunction associated with cerebrovascular disorder and the like.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Psychiatry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à des composés de diamine représentés par la formule générale (I) et à des sels d'addition d'acide de ces composés, ainsi qu'à un agent de protection contre les lésions cérébrales qui contient de tels composés. Dans la formule (I), R1 à R6, qui peuvent être identiques ou différents entre eux, représentent chacun un hydrogène, un halogène, un hydroxy, un alkyle inférieur, un alcoxy inférieur, un acyloxy inférieur, un alcoxycarbonyloxy inférieur, un alkylsulfonyloxy inférieur ou un amino, parmi lesquels l'alkyle inférieur et l'alcoxy inférieur peuvent être chacun substitués par un halogène ou un phényle; R7 et R8, qui peuvent être identiques ou différents entre eux, représentent chacun un alkyle inférieur ou ils peuvent être combinés entre eux pour former un alkylène ayant 1 à 4 atomes de carbone; A et A', qui peuvent être identiques ou différents entre eux, représentent chacun une liaison simple, -O-, -NH-, -NHCO←, -CONH←, -NHCOO←, -NHCONH-, -SONH2← ou -COS←, le symbole '←' représentant une liaison avec Y ou Y'; et Y et Y', qui peuvent être identiques ou différents entre eux, représentent chacun un alkylène inférieur ou un alcénylène inférieur. Ces composés possèdent une excellente action de protection contre les lésions cérébrales, ils sont hautement sûrs et ils peuvent déployer des effets puissants par administration par voie buccale. Des médicaments contenant ces composés sont efficaces dans le traitement ou la prévention de la progression des disfonctionnements cérébraux qui accompagnent les hémorragies cérébrales, les infarctus cérébraux, les hémorragies sous-arachnoïdiennes, les accès ischémiques transitoires cérébraux, ou des troubles cérébrauxvasculaires.
PCT/JP1990/000970 1989-05-30 1990-07-30 Nouveau compose de diamine et agent de protection contre les lesions cerebrales contenant un tel compose WO1992002487A1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
DE69023928T DE69023928T2 (de) 1989-05-30 1990-07-30 DIAMINVERBINDUNGEN UND ARZNEIMITTEL GEGEN CEREBRALE STöRUNGEN DIE DIESE ENTHALTEN.
DK90910895.3T DK0541798T3 (da) 1989-05-30 1990-07-30 Hidtil ukendt diaminforbindelse og cerebralbeskyttende middel indeholdende denne
HU9300228A HU220592B1 (hu) 1989-05-30 1990-07-30 Eljárás diaminszármazékok és ezeket hatóanyagként tartalmazó gyógyszerkészítmények előállítására
KR1019930700135A KR0171569B1 (ko) 1989-05-30 1990-07-30 신규 디아민 화합물 및 이를 함유하는 뇌보호제
EP90910895A EP0541798B1 (fr) 1989-05-30 1990-07-30 Derives de diamine et un medicament protecteur cerebrale les contenant
AU60565/90A AU647034C (en) 1990-07-30 Novel diamine compounds and cerebral protective drugs containing the same
RU9093005056A RU2045522C1 (ru) 1989-05-30 1990-07-30 Диаминовые соединения или их кислотно-аддитивные соли
US07/966,142 US5389630A (en) 1989-05-30 1990-07-30 Diamine compound and brain protecting agent containing the same
ES90910895T ES2081996T3 (es) 1989-05-30 1990-07-30 Nuevos compuestos de diamina y agentes protectores del cerebro que contienen los mismos.
CA002087604A CA2087604C (fr) 1989-05-30 1990-07-30 Composes diamines et medicaments a base de ces composes pour la protection au niveau cerebral
AT90910895T ATE130842T1 (de) 1989-05-30 1990-07-30 Diaminverbindungen und arzneimittel gegen cerebrale störungen die diese enthalten.
FI930360A FI112649B (fi) 1989-05-30 1993-01-28 Menetelmä terapeuttisesti käyttökelpoisten diamiiniyhdisteiden valmistamiseksi
NO930328A NO179322C (no) 1989-05-30 1993-01-29 Analogifremgangsmåte ved fremstilling av terapeutisk aktive diaminforbindelser

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JP1136652A JP2722250B2 (ja) 1989-05-30 1989-05-30 新規なジアミン化合物及びこれを含有する脳機能障害改善剤

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WO1992002487A1 true WO1992002487A1 (fr) 1992-02-20

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US (1) US5389630A (fr)
EP (1) EP0541798B1 (fr)
JP (1) JP2722250B2 (fr)
KR (1) KR0171569B1 (fr)
AT (1) ATE130842T1 (fr)
CA (1) CA2087604C (fr)
DE (1) DE69023928T2 (fr)
DK (1) DK0541798T3 (fr)
ES (1) ES2081996T3 (fr)
FI (1) FI112649B (fr)
HU (1) HU220592B1 (fr)
NO (1) NO179322C (fr)
RU (1) RU2045522C1 (fr)
WO (1) WO1992002487A1 (fr)

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EP0623605A3 (fr) * 1993-05-06 1995-03-01 Bayer Ag Piperazines substituées comme agents antirétroviralin.
US5514680A (en) * 1992-06-22 1996-05-07 The State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University Glycine receptor antagonists and the use thereof
US8044078B2 (en) 2005-09-22 2011-10-25 Sanofi-Aventis Amino-alkyl amide derivatives as CCR3 receptor ligands

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US6017953A (en) * 1993-12-28 2000-01-25 Allergan Sales, Inc. Thromboxane ligands
ES2159622T3 (es) * 1994-01-14 2001-10-16 Azwell Inc Derivado del diazacicloalcanoalquilsulfonamida.
US5602123A (en) 1994-11-02 1997-02-11 Kowa Co., Ltd. Therapeutic agent for myocardial ischemic damages or reperfusion
US5849737A (en) * 1995-04-14 1998-12-15 The Regents Of The University Of California Compositions and methods for treating pain
US5755237A (en) * 1995-06-07 1998-05-26 Rodriguez; Victorio C. Therapeutic use of acetazolamide for the treatment of brain edema
US5944021A (en) * 1995-06-07 1999-08-31 Rodriguez; Victorio C. Therapeutic use of a carbonic anhydrase enzyme inhibitor for the treatment of brain edema
JP3808921B2 (ja) * 1995-11-20 2006-08-16 興和株式会社 細胞接着阻害剤
US6462034B1 (en) 1998-04-03 2002-10-08 Theravance, Inc. Local anesthetic compounds and uses
PE20000354A1 (es) * 1998-04-03 2000-05-20 Advanced Medicine Inc Nuevos compuestos y usos anestesicos locales
SG83735A1 (en) * 1999-07-03 2001-10-16 Advanced Medicine Inc Novel local anesthetic compounds and uses
WO2001025235A1 (fr) 1999-10-01 2001-04-12 Advanced Medicine, Inc. Quinazolinones macrocycliques et leur utilisation en tant qu'anesthesiques locaux
EP1931347A4 (fr) * 2005-08-09 2011-02-16 Ms Science Corp Derives de piperazine
HUP0500877A2 (en) * 2005-09-22 2007-05-29 Sanofi Aventis Amide derivatives as ccr3 receptor ligands, process for producing them, pharmaceutical compositions containing them and their use and intermediates
HUP0500886A2 (en) * 2005-09-23 2007-05-29 Sanofi Aventis Amide derivatives as ccr3 receptor ligands, process for producing them, pharmaceutical compositions containing them and their use
AU2006293635A1 (en) * 2005-09-22 2007-03-29 Sanofi-Aventis Amino-alkyl-amide derivatives as CCR3 receptor liquids
CA2634004A1 (fr) * 2005-12-16 2007-06-21 Neuropharma, S.A. Derives de dibenzene en tant que bloqueurs des canaux calciques
ATE486605T1 (de) 2006-01-27 2010-11-15 Ms Science Corp Piperidin- und piperazin-derivate
EP1986631B1 (fr) * 2006-02-14 2012-04-11 Eastern Virginia Medical School Chélate de thioester de méthoxypolyéthylène glycol et utilisations correspondantes
WO2012176878A1 (fr) * 2011-06-23 2012-12-27 学校法人自治医科大学 Inhibiteur du protéasome

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JPS6075469A (ja) * 1983-06-16 1985-04-27 ベ−リンガ−　インゲルハイム　リミテツド 尿素またはチオ尿素化合物
JPS60181058A (ja) * 1984-02-03 1985-09-14 デグツサ・アクチエンゲゼルシヤフト シアノメチル‐（２‐シアノ‐エチル）‐（３‐ヒドロキシ‐プロピル）‐アミン及びその製法、及び１‐（３‐ヒドロキシ‐プロピル）‐１，４‐ジアゼパン及び１，４‐ビス‐〔３‐（３，４，５‐トリメトキシ‐ベンゾイルオキシ）‐プロピル〕‐ジアゼパンの製法

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JPS60181058A (ja) * 1984-02-03 1985-09-14 デグツサ・アクチエンゲゼルシヤフト シアノメチル‐（２‐シアノ‐エチル）‐（３‐ヒドロキシ‐プロピル）‐アミン及びその製法、及び１‐（３‐ヒドロキシ‐プロピル）‐１，４‐ジアゼパン及び１，４‐ビス‐〔３‐（３，４，５‐トリメトキシ‐ベンゾイルオキシ）‐プロピル〕‐ジアゼパンの製法

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Publication number Priority date Publication date Assignee Title
US5514680A (en) * 1992-06-22 1996-05-07 The State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University Glycine receptor antagonists and the use thereof
US5620979A (en) * 1992-06-22 1997-04-15 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon, Eugene Oregon Glycine receptor antagonists and the use thereof
US5622952A (en) * 1992-06-22 1997-04-22 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon, Eugene Oregon Glycine receptor antagonists and the use thereof
EP0623605A3 (fr) * 1993-05-06 1995-03-01 Bayer Ag Piperazines substituées comme agents antirétroviralin.
US8044078B2 (en) 2005-09-22 2011-10-25 Sanofi-Aventis Amino-alkyl amide derivatives as CCR3 receptor ligands

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Publication number Publication date
US5389630A (en) 1995-02-14
NO930328D0 (no) 1993-01-29
NO930328L (no) 1993-01-29
DE69023928D1 (de) 1996-01-11
NO179322B (no) 1996-06-10
HU220592B1 (hu) 2002-03-28
FI930360A0 (fi) 1993-01-28
JP2722250B2 (ja) 1998-03-04
NO179322C (no) 1996-09-18
DE69023928T2 (de) 1996-04-18
JPH032144A (ja) 1991-01-08
EP0541798A4 (fr) 1994-04-13
AU6056590A (en) 1992-03-02
KR0171569B1 (ko) 1999-05-01
FI112649B (fi) 2003-12-31
HUT63143A (en) 1993-07-28
RU2045522C1 (ru) 1995-10-10
ATE130842T1 (de) 1995-12-15
EP0541798A1 (fr) 1993-05-19
EP0541798B1 (fr) 1995-11-29
AU647034B2 (en) 1994-03-17
FI930360A7 (fi) 1993-01-28
CA2087604C (fr) 2000-04-18
HU9300228D0 (en) 1993-04-28
DK0541798T3 (da) 1995-12-27
ES2081996T3 (es) 1996-03-16

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